Various kinds of medicine are used in medication. Some of them turn to be positive ions (cations) in vivo condition. Nowadays, the study on the transporter (transiport protain) that exist in cell membrane and contribute to transitivity into tissue, absorption, renal excretion, and biliary excretion is rapidly in progress. Among the transporters, an organic cation transporter (OCT) is important to transport cationic medicine.
Recent research has make it clear that OCT3 exist in the kidney, small intestine, lung, heart, and brain as well as placenta.
Nucleoside analogues, quinolines, tricyclic compound is reported as OCT3 inhibitor, but these are difficult to use as medicine because of the problem such as side effect. Guanidine derivative is reported as OCT3 inhibitor (nonpatent literature 1). However, IC50 of famotidine and cimetidine (Histamine H2-receptor antagonist) is 20 μM and 240 μM respectively and IC50 of Ramosetron and granisetron (setron compound) are both less than 100 μM.
Guanidine derivative and its production method is disclosed, for example, in the following literature: JP H2-288860, JP H3-157308, JP H3-291267, JP H5-9173, JP H9-67342, JP H9-67342, JP H9-95477, JP H9-278767, JP H10-120666, JP H10-158233, JP H10-237073, JP 2004-285073, JP 2005-29479, JP 2007-504176, JP 2007-523113, JP 2008-507571, JP 2009-530352, JP 2011-513477, JP 2000-281665, WO 9842690, and EP-A0869120. As disclosed in these literature, Guanidine is already known as active components for the insecticide, cosmetics, medicine, and drug carrier, etc.
On the other hand, WO 2005-084707 (Patent Literature21) discloses the remedy of mental disorder containing an suppressant of organic cation transporter OCT3 gene expression as an active ingredient. US 2007-0136828 (Patent Literature 22) discloses the remedy of depression by inhibiting OCT3 function, containing alkylamine-catechol derivative, quinoline derivative, and bis-quinoline derivative as active ingredients.
WO 2001-93863 pamphlet (Patent Literature 24) discloses the treatent of depression and depressive symptom consisting famotidine as an active ingredient. U.S. Pat. No. 6,403,645 (Patent Literature 25) discloses the remedy of depression consisting transporter Uptake2 (OCT and PMAT).
According to these literature, the treatment of depression and depressive symptom by inhibiting an organic cation transporter OCT3 is established.